In spite of constant challenge from microbes and inorganic particles in inhaled air, the healthy lung maintains a sterile gas exchange surface without invoking inflammation. Constitutively expressed antimicrobial peptides/proteins are important part of the first line of defense, rapidly killing inhaled pathogens and/or facilitating their clearance by alveolar macrophages. Lysozyme is the most abundant cationic protein in the airway surface liquid and accounts for most of the microbicidal activity in the unchallenged lungs. In the first grant cycle, we demonstrated that lysozyme plays an important role in killing of both Gram-positive and Gram-negative bacteria in vivo and that muramidase might not be required for bacterial killing, but may be important in modulating inflammation. The current application will extend these important preliminary findings by testing the central hypothesis that lysozyme plays a dual role in pulmonary innate immunity by (1) directly killing bacteria and (2) rapidly degrading pro-inflammatory bacterial cell wall components (peptidoglycan and its fragments). Both lysozyme loci, LysM and LysP, will be disrupted and the mouse model used to test following hypotheses: 1) that deletion of both LysM and LysP loci will lead to persistent inflammation and infection arising from a reduced ability/inability to kill low levels of inhaled microorganisms and from undegraded peptidoglycan, 2) that the bactericidal properties of lysozyme map to the N- and C-terminal regions of the protein and that these [unreadable]bactericidal domains[unreadable] account for much or all of the rapid killing of bacteria, and 3) that the muramidase property of lysozyme plays a critical role in pulmonary host defense by rapidly degrading pro-inflammatory components (peptidoglycan and its fragments) of the bacterial cell wall. These studies will provide new insight into the role of lysozyme in innate host defense of the lungs and the mechanisms by which lysozyme enhances bacterial killing and modulates the inflammatory response to infection.